Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/96—Esters of carbonic or haloformic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C46/00—Preparation of quinones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
  • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C50/00—Quinones
  • C07C50/10—Quinones the quinoid structure being part of a condensed ring system containing two rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C50/00—Quinones
  • C07C50/24—Quinones containing halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C50/00—Quinones
  • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
  • C07C50/32—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C68/00—Preparation of esters of carbonic or haloformic acids

Definitions

• the invention relates to naphthalene derivatives which are useful in the treatment of certain dermatological conditions and inhibiting lipoxygenase activity, particularly 5-lipoxygenase activity which makes the compounds useful for topical treatment of inflammatory states.
• This invention also relates to pharmaceutical compositions useful in relieving the effects of certain chronic recurrent papulosquamous dermatoses, e.g., psoriasis.
• This invention also relates to a process for preparing compounds of this invention.
• Psoriasis is a skin disease characterized in part by excessive proliferation of cells of the epidermis which remain strongly adherent and build up into a scaley plaque typical of the disease.
• therapies such as corticosteroids, vitamin A derivatives (retinoids), cancer chemotherapeutic agents (methotrexate, razoxane), coal tar and anthralin preparations, and psoralen-u.v. irradiation (PUVA) are effective in controlling the disease to a certain extent, they can cause numerous and sometimes severe undesirable side effects including renal irritation, hepatic toxicity, and erythema.
• naphthoquinone derivatives are known to be useful in treating psoriasis. See, for example, U.S. Patent Nos. 4,229,478, 4,466,981 and 4,593,120 and British Patent No. 1,243,401. Carbamate and carbonate derivatives of naphthalene having insecticidal properties are known. See, for example, U.S. Patent Nos. 2,383,392, 3,958,006 and 4,181,741.
• the compounds of the instant invention are also effective antipsoriatic agents.
• Compounds of formula (I) provide prolonged activity in the treatment of psoriasis because of their stability upon application and slow conversion to compounds of formula (XII) and (XIII). Further, the compounds of the present invention are more stable in the topical formulations normally used.
• the present invention relates to a compound of the formula wherein: R1 is lower alkoxy of one to six carbon atoms or phenoxy optionally substituted by one or two substituents chosen from lower alkyl of one to four carbon atoms, lower alkoxy of one to four carbon atoms and halo; R2 is hydrogen, lower alkyl of one to six carbon atoms, lower alkoxy of one to six carbon atoms, phenyl, phenoxy or phenyl-lower-alkyl, wherein the phenyl ring of the phenyl, phenoxy or phenyl-lower-alkyl group is optionally substituted by one or two substituents chosen from lower alkyl of one to four carbon atoms, lower alkoxy of one to four carbon atoms and halo; R3 is hydrogen, halo, lower alkyl of one to six carbon atoms, lower alkoxy of one to six carbon atoms, phenyl, phenyl-lower-al
• Another aspect of the present invention relates to a pharmaceutical composition in a form suitable for administration to mammals comprising a compound of the formula (I).
• Yet another aspect of the invention is a novel process for preparing compounds of formula (I).
• Compounds of formula (VIII) and (IX) infra which are intermediates for compounds of formula (Ia), (Ib), (Ic) and (Id) infra, are prepared by carefully controlled hydrolysis of the compound of formula (VII).
• Compounds of formula (Ia), (Ib), (Ic) and (Id) are prepared by reacting compounds of formula (VIII) and (IX) with the appropriate reactant.
• Compounds of formula (Ie) and (If) are prepared by reacting compounds of formulae (VI) and (XX) with the appropriate reactants.
• Yet another aspect of the invention is a process for preparing the pharmaceutical compositions comprising an effective amount of a compound of formula (I).
• Another aspect of the invention relates to the compounds for use in relieving inflammatory diseases, such as the condition of psoriasis in mammals.
• the present invention relates to a compound of the formula wherein: R1 is lower alkoxy of one to six carbon atoms or phenoxy optionally substituted by one or two substituents chosen from lower alkyl of one to four carbon atoms, lower alkoxy of one to four carbon atoms and halo; R2 is hydrogen, lower alkyl of one to six carbon atoms, lower alkoxy of one to six carbon atoms, phenyl, phenoxy or phenyl-lower-alkyl, wherein the phenyl ring of the phenyl, phenoxy or phenyl-lower-alkyl group is optionally substituted by one or two substituents chosen from lower alkyl of one to four carbon atoms, lower alkoxy of one to four carbon atoms and halo; R3 is hydrogen, halo, lower alkyl of one to six carbon atoms, lower alkoxy of one to six carbon atoms, phenyl, phenyl
• Another aspect of the present invention relates to a pharmaceutical composition in a form suitable for topical administration to mammals comprising a compound of the formula (I).
• the compounds of formula (I) may be divided into subgroups (Ia), (Ib), (Ic), (Id), (Ie) and (If).
• R4 is lower alkyl of one to three carbon atoms such as methyl, ethyl, n-propyl and i-propyl, with methyl being most preferred.
• An even more specific embodiment of the instant invention are compounds of formula (I) wherein m is 1 and R3 is at the 6-position and is bromo, chloro, fluoro, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and i-butoxy, with chloro being preferred.
• a preferred embodiment of the invention are compounds of formula (I) wherein R3 is hydrogen.
• Another embodiment of the invention are compounds wherein m is 2 and the two R3s are at the 6 and 7 positions and are lower alkyl, lower alkoxy or halo with R3 being methyl being preferred.
• alkyl is intended to mean alkyl groups containing one to seven carbon atoms including straight chain groups, or branched chain groups. Illustrative of such groups are for example, methyl, ethyl, n-propyl, i-propyl, n-hexyl, 2-methylpentyl, n-heptyl, 2,2-dimethylbutyl and 3,3-dimethylpentyl.
• lower alkyl refers to alkyl groups of one to six carbon atoms as defined above.
• lower alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, 2,2-dimethylpropyl and t-hexyl.
• phenyl-lower-­alkyl refers to an optionally substituted phenyl ring attached to an alkylene chain of one to six carbon atoms.
• lower alkoxy refers to a straight or branched chain aliphatic group of one to six carbon atoms having bonded thereto an oxygen moiety.
• lower alkoxy are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy and n-pentyloxy.
• Phenyl-lower-alkoxy refers to a phenyl ring attached to an alkylene chain of one to six carbon atoms having bonded thereto an oxygen atom.
• phenyl-­lower-alkoxy are benzyloxy, 4-chlorophenylethoxy and phenyl-n-propoxy and 2-methoxyphenyl-n-hexyloxy.
• sterically hindered refers to alkyl groups wherein branching occurs at the carbon adjacent to or one carbon removed from the carbonyl group or to optionally substituted phenyl.
• Optionally substituted phenyl refers to a phenyl (or phenoxy) ring optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy and halo unless otherwise defined.
• halo refers to fluoro, chloro, and bromo.
• the compounds of formula (I) are defined to show, in part, R1 as lower alkoxy and R4 as lower alkyl.
• R1 and -OR4 both represent lower alkoxy.
• the compounds of formula (I) exist as two pairs of regioisomers (position isomers) represented by the formulas (Ia) and (Ib), and (Ic) and (Id).
• the isomers may be separated at any stage of the preparation of (Ia), (Ib), (Ic) and (Id), but it is preferred to separate the isomeric mixture of compounds of formula (Ia) and (Ib).
• the individual isomers of compounds of formula (Ic) and (Id) may then be prepared.
• the isomers may be separated by crystallization, normal or reverse phase HPLC or other partition chromatographic techniques, and the like.
• compositions of the present invention may be formulated for administration in any convenient way by analogy with other topical compositions adapted for use in mammals. These compositions may be presented for use in any conventional manner with the air of any of a wide variety of pharmaceutical carriers or vehicles.
• the naphthalenes of formula (I) may be formulated with suitable pharmaceutical vehicles known in the art to form particularly effective topical compositions.
• An effective amount of the naphthalene compound is about 0.001%w to about 10%w of the total formulated composition.
• the rest of the formulated composition will be about 90%w to about 99.999%w of a suitable excipient which may include a pharmaceutically acceptable solvent and other pharmaceutically acceptable additives to form a topically effective pharmaceutical formulation.
• a pharmaceutically acceptable solvent is one which is substantially non-toxic and non-irritating under the conditions used and may be readily formulated into any of the classical drug formulations such as powders, creams, ointments, lotions, gels, foams, aerosols, solutions and the like.
• Particularly suitable solvents include water,ethanol, acetone, glycerine, propylene carbonate, dimethylsulfoxide (DMSO), and glycols such as 1,2-­propylene diol, i.e., propylene glycol, 1,3-propylene diol, polyethylene glycol having a molecular weight of from 100 to 10,000, dipropylene glycol, etc. and mixtures of the aforementioned solvents with each other.
• a topical cream may be prepared as a semi-solid emulsion of oil in water or water in oil.
• a cream base formulation by definition is an emulsion, which is a two-phase system with one liquid (for example fats or oils) being dispersed as small globules in another substance (e.g., a glycol-water solvent phase) which may be employed as the primary solvent for the naphthalenes therein.
• the cream formulation may contain fatty alcohols, surfactants, mineral oil or petrolatum and other typical pharmaceutical adjuvants such as anti-oxidants, antiseptics, or compatible adjuvants.
• a typical cream base formulation is as follows: Water/glycol mixture (15% or more glycol) 50 - 99 parts by weight Fatty Alcohol 1 - 20 Non-ionic Surfactant 0 - 10 Mineral Oil 0 - 10 Typical Pharmaceutical Adjuvants 0 - 5 Active Ingredients 0.001 - 10
• the naphthalenes of formula (I) may also be formulated as topical ointments.
• a "classical" ointment is a semisolid anhydrous composition which may contain mineral oil, white petrolatum, a suitable solvent such as a glycol and may include propylene carbonate and other pharmaceutically suitable additives such as surfactants, for example Span and Tween, or wool fat (lanolin), along with stabilizers such as antioxidants and other adjuvants as mentioned before.
• a suitable topical "non-classical” anhydrous, water washable “ointment type” base is described in U.S. Patent No. 3,592,930 to Katz and Neiman.
• a representative composition of this invention utilizing such base is as follows: Glycol Solvent 40 - 35 parts by weight Fatty Alcohol 15 - 45 Compatible Plasticizer 0 - 15 Compatible Coupling Agent 0 - 15 Penetrant 0 - 20 Active Ingredients 0.001 - 10.0
• Another aspect of the invention is a method for relieving the condition of psoriasis in a mammal by topically administering a composition containing a compound of formula (I) wherein R1, R2, R3, X, Y and m are as defined above.
• a composition containing a compound of formula (I) wherein R1, R2, R3, X, Y and m are as defined above is combatted by contacting the inflamed areas with a therapeutically effective amount of the naphthalene-containing compositions of this invention, that is, an amount which results in a lessening of the epidermal cell proliferation (an anti-psoriatic effect).
• the naphthalenes are first formulated to prepare a suitable pharmaceutical formulation, as discussed hereinabove, which is then placed in contact with the afflicted area(s).
• An effective amount of the naphthalene compound will depend upon the particular condition and the mammal receiving the treatment and will vary between 0.001% to 10% by weight of the pharmaceutical composition and preferably will be between 0.01% and 1% by weight of the formulation.
• a therapeutically effective and non-side effect producing amount i.e. enough to affect an anti-psoriatic response, but not enough to adversely effect the recipient, is applied to the afflicted area(s).
• the compounds of this invention are also useful for treating mammals having a variety of disease states caused by lipoxygenase activity, particularly 5-lipoxygenase activity.
• compositions of the present invention have also been found to be active when administered orally. Accordingly, the compositions may be formulated for oral, parenteral and otherwise systemic forms. Depending on the intended mode, the compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages.
• the compositions will include a conventional pharmaceutical carrier or excipient and an active compound of Formula I and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
• the amount of active compound administered will of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
• compositions contain 0.01-95% by weight of active ingredient, with the balance one or more acceptable non-toxic carriers.
• the percentage of active ingredients will, of course, depend upon the dosage form and the mode of administration.
• conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used.
• the active compound as defined above may be formulated as suppositories using, for example, polyalkylene glycols, for example, propylene glycol, as the carrier.
• Liquid pharmaceutically administerable compositions can, for example, be prepared by dissolving, dispersing, etc.
• compositions to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
• auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
• Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences , Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975.
• the composition or formulation to be administered will, in any event, contain a quantity of the active compound(s) in an amount effective to alleviate the symptoms of the subject being treated.
• a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
• excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
• Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
• Such compositions may contain 2%-95% active ingredient, preferably 5-25%.
• Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
• Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
• Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like.
• the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
• binders and carriers include, e.g. polyalkalene glycols or triglycerides. Such suppositories may be formed from mixtures containing active ingredient in the range of 0.1%-10%; preferably 0.5 to 2%.
• In vitro lipoxygenase inhibiting activity of the compounds of this invention are determined by the standard Human Polymorphonuclear Leukocytes assay. This assay is a modification of that described by O. Radmark, C. Malmsten, and B. Samuelsson in FEBS Letter , 110 , 213-215, 1980.
• In vivo lipoxygenase inhibiting activity of the compounds of this invention are determined by the arachidonic acid mouse ear inflammation assay as described by J. M. Young, D. A. Spires, C. J. Bedord, B. Wagner, S. J. Ballaron and L. M. DeYoung in Journal of Investigative Dermatology , 82 , 367-371, 1984.
• the compounds of formula (Ia), (Ib), (Ic) and (Id) may be prepared from the compounds of formula (XII) and (XIII), which are prepared as shown below in Reaction Sequence I. wherein R1, R2, R3, R4 and m are as defined above and R8 is alkyl, phenyl or benzyl.
• the 5,8-dihydro derivative of the compound of formula (II) is recovered and treated with an oxidizing agent such as sodium dichromate, sodium nitrite, manganese dioxide and the like to form compounds of formula (II) wherein R2 is hydrogen.
• Compounds of formula (II) wherein R2 is alkyl, optionally substituted phenyl or phenylalkyl may be prepared by reacting the naphthoquinone of formula (II) wherein R2 is hydrogen with an acid of the formula R2COOH wherein R2 is as defined above but is other than hydrogen.
• Compounds for formula (III) are prepared by bubbling chlorine gas into a solution of compound of formula (II) dissolved in a solvent such as glacial acetic acid, nitrobenzene, carbon tetrachloride and the like, preferably glacial acetic acid at room temperature.
• a solvent such as glacial acetic acid, nitrobenzene, carbon tetrachloride and the like, preferably glacial acetic acid at room temperature.
• the compound of formula (III) which may be isolated by known means, dissolved in a solvent such as acetic acid is treated with a suitable catalyst such as sodium acetate,iodine, iron(III)chloride, dimethylformamide or lower alcohols, for example methanol or ethanol, with heating under reflux for 1/2 to 4 hours, preferably for 1 to 2 1/2 hours to yield compounds of formula (IV).
• Compounds of formula (V) are prepared by reacting compound of formula (IV) with an alkali metal alkoxide or phenoxide such as sodium alkoxide or phenoxide, e.g., sodium methoxide or phenoxide in an anhydrous solvent such as methanol, dimethylformamide and the like, the solvent if an alcohol being chosen according to the length of the alkyl chain on the alkoxy group e.g. sodium methoxide in methanol, sodium ethoxide in ethanol and the like.
• the reaction mixture is heated at a temperature of about 0°C to 60°C, preferably about 20°C to 30°C, for 3 to 24 hours, preferably about 10 to 18 hours.
• Compounds of formula (V) are recovered by conventional means such as by crystallization.
• Compounds of formula (IV) may also be converted to compounds of formula (V), by treatment with an alcoholic solution of a strong base such as potassium hydroxide in methanol and then alkylating the intermediate compound of formula (IX), infra, using the appropriate halide or an alcohol as is described hereinafter under Reaction Sequence II.
• a strong base such as potassium hydroxide in methanol
• Compounds of formula (VII) are prepared from compounds of formula (V) by first hydrogenating to form compounds of formula (VI).
• the compound of formula (V) is hydrogenated in a hydrogen atmosphere in the presence of a catalyst such as palladium on charcoal, or alternatively using transfer hydrogenation conditions with, for example, cyclohexadiene and a catalyst such as palladium on charcoal.
• a catalyst such as palladium on charcoal
• Polar solvents such as tetrahydrofuran, dimethylformamide or ethanol are preferred, most preferably tetrahydrofuran.
• the compounds of formula (V) are reduced with sodium hydrosulfite in an alcoholic solvent, preferably methanol or ethanol, to give the compound of formula (VI).
• the compound of formula (VI) is then reacted with an acylating agent such as an appropriate anhydride, for example acetic anhydride, propanoic anhydride, benzoic acid anhydride and the like, preferably acetic anhydride, in the presence of an organic base such as pyridine, triethylamine and the like or an inorganic base such as sodium hydroxide, potassium carbonate, sodium bicarbonate and the like, preferably triethylamine, in an inert solvent such as benzene, acetonitrile, ethyl acetate, tetrahydrofuran, diethyl ether, chloroform, methylene chloride and the like.
• an acylating agent such as an appropriate anhydride, for example acetic anhydride, propanoic anhydride, benzoic acid anhydride and the like, preferably acetic anhydride, in the presence of an organic base such as pyridine, triethylamine and the like or
• the compounds of formula (VIII) and (IX), i.e., compounds wherein either X or Y is hydrogen and the other X or Y is acyloxy, preferably acetyloxy, are prepared from the compounds of formula (VII) by a novel hydrolysis process wherein the pH of the reaction mixture is carefully controlled and maintained at pH 7.5 to 9.5, preferably pH 8-9. If general hydrolysis conditions are employed both ester groups are removed from the compound of formula (VII) to form the compound of formula (VI) which will revert to the 1,4-naphthoquinone under aerobic conditions.
• the reaction is monitored by, e.g., thin layer chromatography. Additional buffer is added, if necessary, to maintain pH 8-9.
• the compounds of formula (VIII) and (IX) are recovered by, e.g., extraction and purified by recrystallization.
• the mixture of compounds of formula (VIII) and (IX) may be separated by preparative high pressure liquid chromatography using silica gel and eluting with suitable solvents, for example anhydrous methanol/hexane.
• Compounds of formula (X) or (XI) may be prepared by reacting a compound of formula (VIII) or (IX) respectively with an alkylating agent such as an alkyl tosylate, an alkyl mesylate or an alkyl or phenylalkyl halide such as benzyl bromide, i-propyl bromide, n-butyl bromide, phenylethyl bromide and the like.
• an alkylating agent such as an alkyl tosylate, an alkyl mesylate or an alkyl or phenylalkyl halide such as benzyl bromide, i-propyl bromide, n-butyl bromide, phenylethyl bromide and the like.
• Compounds of formula (X) or (XI) may also be prepared by reacting the compound of formula (VIII) or (IX) with a diazoalkane such as diazomethane, diazoethane, diazophenylmethane and the like.
• a diazoalkane such as diazomethane, diazoethane, diazophenylmethane and the like.
• a solution of the compound of formula (VIII) or (IX) in a solvent such as ether is treated with a solution of diazomethane in a solvent such as ether generated in situ from N-methyl-N-nitroso-p-toluenesulfonamide (Diazald®).
• the compound of formula (X) or (XI) is recovered by evaporation followed by flash chromatography over silica gel.
• Compounds of formula (XII) or (XIII) are prepared from the compounds of formula (X) and (XI) by hydrolysis of the ester group -OC(O)CH3.
• the compound of formula (X) or (XI) is dissolved in a water-miscible solvent such as ethanol containing a base such as sodium hydroxide or potassium carbonate, optionally in the presence of water, and stirred at a temperature of about 0°C to 80°C, preferably about 25°C, for about 1 to 24 hours, preferably about 6 hours.
• a water-miscible solvent such as ethanol containing a base such as sodium hydroxide or potassium carbonate
• pairs compounds (VIII) and (IX), (X) and (XI), and (XII) and (XIII) as intermediates to the compounds of formula (Ia), (Ib), (Ic) and (Id) may also exist as pairs of regioisomers. As with the regioisomers (Ia) and (Ib), or (Ic) and (Id), they may be separated at any stage in the preparation of the latter compounds.
• DBU and Diazald® are available from, i.a., Aldrich Chemical Co.
• the alkyl and arylalkyl halides are readily available from, i.a., Aldrich Chemical Co. or may be made by methods well known in the art.
• the butadiene intermediate such as 2-chloro-1,3-­butadiene (chloroprene), 2-methyl-1,3-butadiene(isoprene), 2-ethyl-1,3-butadiene 1-methoxy-1,3-butadiene, 2-phenyl-1,3-butadiene, 1-phenyl-1,3-butadiene and the like are available from, i.a., Pfaltz and Bauer Chemical Co.
• 2-Bromo-1,3-butadiene and 2-fluoro-1,3-butadiene may be prepared by methods well known in the art, for example, by the methods discussed in J. Am. Chem. Soc., 55 786 (1933) and U. S. Patent No. 2,401,850, respectively.
• the acid anhydrides are commercially available from, i.a., Aldrich Chemical Co. or if not available may be prepared by condensing the appropriate acid in the presence of acetic anhydride or acetyl chloride containing a trace of phosphoric acid. The anhydride is recovered by distillation or crystallization.
• the compound of formula (XIV) is prepared by acylating the compound of formula (II) in the presence of a Lewis acid such as boron trifluoride:etherate or a strong inorganic acid, such as perchloric acid, and the like. This reaction is commonly known as the Theile-Winter reaction.
• the acylating agent is an acid anhydride such as acetic anhydride, propanoic anhydride and the like, preferably acetic anhydride.
• the compound of formula (XIV) wherein R2 is hydrogen may be converted to the compound of formula (XIV) wherein R2 is alkyl, optionally substituted phenyl or phenylalkyl by reaction with a peracid anhydride of the formula (R2CO2)2 wherein R2 is as defined above and is other than hydrogen.
• a solution of the unsubstituted compound in a solvent such as glacial acetic acid is heated to 70°-120°C, preferably from 75°-100°C and an ethereal solution of the anhydride is added dropwise over 1 to 6 hours, preferably over 2 to 4 hours.
• the compound of formula (XIV) wherein R2 is alkyl, optionally substituted phenyl or phenylalkyl is recovered by precipitation.
• the compound of formula (XIV) wherein R2 is hydrogen or alkyl, optionally substituted phenyl or phenylalkyl is then hydrolyzed by treatment with an alkali metal alkoxide in an alcohol, such as sodium methoxide in methanol, followed by treatment with aqueous hydrochloric acid to form the compound of formula (XV).
• the compound of formula (XV) is then converted to the compound of formula (V) where R1 is lower alkoxy or optionally substituted phenoxy, and R2 is hydrogen, lower alkyl, optionally substituted phenyl or optionally substituted phenylalkyl, by reaction with an appropriate halide and base by reaction with an appropriate halide and base, or an appropriate alcohol, for example methanol, ethanol and the like, under acid catalysis.
• the compound of formula (XV) is reacted with an alkyl halide, e.g. an alkyl bromide or alkyl iodide in a solvent such as tetrahydrofuran and the like.
• an alkyl halide e.g. an alkyl bromide or alkyl iodide
• a solution of 1,5-diazobicyclo[5.4.0]undec-5-ene (DBU) in a solvent such as tetrahydrofuran is added dropwise.
• the precipitate of DBU-hydrogen halide which forms is removed by filtration and the compound of formula (V) is recovered by evaporation.
• the compound of formula (V) may also be prepared by reacting the compound of formula (XV) with an alcohol. To a solution of the compound of formula (XV) in the appropriate alcohol of formula R1OH is added boron trifluoride etherate. The solution is heated from 50° to 100°C, preferably from 60° to 80°C for 1/2 hour to 4 hours, preferably for 1 to 3 hours. The compound of formula (V) is recovered by filtration.
• Compounds of formula (XVIII) are prepared by reacting the compound of formula (II) with chlorine or bromine, preferably chlorine.
• chlorine gas is bubbled into a solution of the compound of formula (II) dissolved in a solvent such as glacial acetic acid, nitrobenzene, carbon tetrachloride and the like, preferably glacial acetic acid at reflux temperature in the presence of a suitable catalyst such as sodium acetate, iodine, iron(III)chloride, dimethylformamide or lower alcohols, for example methanol or ethanol, preferably about 0.1 molar equivalent of iodine.
• a solvent such as glacial acetic acid, nitrobenzene, carbon tetrachloride and the like, preferably glacial acetic acid at reflux temperature in the presence of a suitable catalyst such as sodium acetate, iodine, iron(III)chloride, dimethylformamide or lower alcohols, for example methanol or ethanol, preferably about
• Compounds of formula (XIX) are prepared from the 2,3-dihalonaphthoquinone of formula (XVIII), preferably a 2,3-dichloro-1,4-naphthoquinone.
• the compound of formula (XVIII) is reacted with an alkali metal alkoxide or phenoxide of formula R1M, where M is an alkali metal.
• the reaction is conducted in an inert organic solvent such as tetrahydrofuran, dimethylsulfoxide, dimethylformamide and the like, or preferably in an alcohol of formula R1H, at temperatures from about 20°C to about 100°C, preferably about 60°-70°C, for a time sufficient to assure completeness of reaction, i.e., for about 30 minutes to about 8 hours, preferably about 1-2 hours.
• an inert organic solvent such as tetrahydrofuran, dimethylsulfoxide, dimethylformamide and the like, or preferably in an alcohol of formula R1H
• R1H preferably about 60°-70°C
• Compounds of formula (XIX) are then reduced to compounds of formula (VI).
• the compound of formula (XIX) may be hydrogenated in a hydrogen atmosphere in the presence of a catalyst such as palladium on charcoal, or alternatively reduced using transfer hydrogenation conditions with, for example, cyclohexadiene and a catalyst such as palladium on charcoal.
• a catalyst such as palladium on charcoal
• Polar solvents such as tetrahydrofuran, dimethylformamide or ethanol are preferred, most preferably tetrahydrofuran.
• the compounds of formula (XIX) are reduced with sodium hydrosulfite in an alcoholic solvent, for example methanol or ethanol, to give the compound of formula (VI) where R1 and R2 are the same and are lower alkoxy or optionally substituted phenoxy.
• Reaction Sequence VA the preparation starts from the compound of formula (XII), prepared as shown in Reaction Sequences I, II and III.
• the compound of formula (XII) is first converted to an activated carbonyl derivative of formula (XVI), in which Z is a leaving group chosen to be capable of displacement by an amine of formula HNR6R7.
• Z may be halo, 1-imidazolyl, trichloromethoxy, optionally substituted phenoxy, such as 2,4-dichlorophenoxy, 4-methoxyphenoxy, and the like.
• the compound of formula (XVI) where Z is chloro is made by reaction of a compound of formula (XII) with from 1-10 molar equivalents, preferably about 2 molar equivalents, of phosgene in an inert organic solvent as defined above, preferably benzene.
• the reaction takes place in the presence of from 1-5 molar equivalents, preferably about 2 molar equivalents of a tertiary organic base such as triethylamine or preferably pyridine.
• the reaction is conducted at from 0°-50°C., preferably about 25°C, for about 1-72 hours, preferably about 18 hours, and then filtered. Evaporation of the filtrate under vacuum affords the compound of formula (XVI) where Z is chloro.
• Compounds of formula (Ia) are then prepared by treating the appropriately substituted compound of formula (XVI) with an appropriate amine of formula HNR6R7, thereby converting the -OC(O)Z group to the corresponding carbamate.
• the compound of formula (XVI) is dissolved in an inert solvent as defined above, preferably tetrahydrofuran, and reacted with from about 2-5 molar equivalents, preferably about 2-3 molar equivalents, of the appropriate amine of formula HNR6R7 in solution in an inert solvent as defined above, preferably tetrahydrofuran.
• the reaction takes place at a temperature of about 0°-40°C., preferably about 20°-30°C., for about 1-10 hours, preferably about 4-6 hours.
• the product compound of formula (Ia) is isolated by conventional means such as chromatography.
• reaction is carried out in the presence of from 1-5 molar equivalents, preferably 2 molar equivalents, of a tertiary organic base or an inorganic base, as defined above.
• the compound of formula (XVI) is then reacted with from 1-4 molar equivalents, preferably about 1.2 molar equivalents, of the appropriate amine of formula HNR6R7 in an inert organic solvent, as defined above.
• compounds of formula (Ia) are made directly from compounds of formula (XII), by reaction with an appropriately substituted carbamoyl chloride of formula ClC(O)NR6R7, where R6 and R7 cannot both be hydrogen.
• an inert organic solvent as defined above, preferably tetrahydrofuran, and reacted with from 1-4 molar equivalents, preferably about 1.2 molar equivalents, of the appropriate carbamoyl chloride of formula ClC(O)NR6R7 in the presence of a tertiary organic base or inorganic base as defined above.
• the reaction takes place at a temperature of about 0°-40°C., preferably about 20°-30°C., for about 1-10 hours, preferably about 4-6 hours.
• the product of formula (Ia) is isolated by conventional means such as chromatography.
• compounds of formula (Ia) where R6 is not hydrogen and R7 is hydrogen can be made by reacting a compound of formula (XII) with an appropriately substituted isocyanate of formula R6NCO where R6 is not hydrogen.
• the compound of formula (XII) is dissolved in an inert organic solvent as defined above, preferably tetrahydrofuran, and reacted with from 1-5 molar equivalents, preferably about 1.2 molar equivalents, of an isocyanate of formula R6NCO in the presence of about 0.2 molar equivalents of 4-dimethylaminopyridine.
• the reaction takes place at a temperature of about 10°-70°C., preferably about 40°-60°C., for about 4-48 hours, preferably about 20-28 hours.
• the product of formula (Ia) is isolated by conventional means.
• the activated carbonyl derivative of formula (XVI), prepared as shown in Reaction Sequence VA above, is reacted with an alcohol of formula R5OH.
• the compound of formula (XVI) is dissolved in an alcohol of formula R5OH containing from 1-5 molar equivalents, preferably about 2 molar equivalents of a tertiary organic base such as triethylamine or preferably pyridine.
• the reaction takes place at a temperature of about 0°-40°C., preferably about 20°-30°C., for about 1-10 hours, preferably about 4-6 hours.
• the product compound of formula (Ic) is isolated by conventional means such as chromatography.
• the compound of formula (XII) is reacted as shown above in Reaction Sequence VA with an appropriate alkyl or aryl chloroformate, or alternatively with an appropriate dialkyl or diaryl dicarbonate, in the presence of a tertiary organic base.
• the compound of formula (XII) is dissolved in an inert solvent as defined above, preferably tetrahydrofuran, and reacted with a chloroformate and a tertiary organic base, preferably triethylamine.
• the reaction is conducted at a temperature of about 0-50°C, preferably about 20°-30°C, for about 4-48 hours, preferably about 16-24 hours, giving the compound of formula (Ic), which is isolated by conventional means such as chromatography.
• the compounds of formula (Ib) and (Id) are prepared in the manner shown above for the compounds of formula (Ia) and (Ic), replacing the starting materials of formula (XII) and (XVI) with the compounds of formula (XIII) and (XVII) respectively.
• Reaction Sequence VIIA the preparation starts from the compound of formula (VI), prepared as shown in Reaction Sequences I and IV.
• the compound of formula (Ie) where X is -C(O)NR6R7
• the compound of formula (VI) is first converted to an activated carbonyl derivative of formula (XX), in which Z is a leaving group chosen to be capable of displacement by an amine of formula HNR6R7.
• Z may be halo, 1-imidazolyl, trichloromethoxy, optionally substituted phenoxy, such as 2,4-dichlorophenoxy, 4-methoxyphenoxy, and the like.
• the compound of formula (XX) where Z is chloro is made by reaction of a compound of formula (VI) with from 1-10 molar equivalents, preferably about 2 molar equivalents, of phosgene in an inert organic solvent such as benzene, acetonitrile, ethyl acetate, tetrahydrofuran, diethyl ether, chloroform, methylene chloride and the like, preferably benzene.
• the reaction takes place in the presence of from 1-5 molar equivalents, preferably about 2 molar equivalents of a tertiary organic base such as triethylamine or preferably pyridine.
• the reaction is conducted at from 0°-50°C., preferably about 20°-30°C, for about 1-72 hours, preferably about 16-24 hours, and then filtered. Evaporation of the filtrate under vacuum affords the compound of formula (XX) where Z is chloro.
• Compounds of formula (Ie) are then prepared by treating the appropriately substituted compound of formula (XX) with an appropriate amine of formula HNR6R7, thereby converting the -OC(O)Z group to the corresponding carbamate.
• the compound of formula (XX) is dissolved in an inert solvent as defined above, preferably tetrahydrofuran, and reacted with from about 2-5 molar equivalents, preferably about 2-3 molar equivalents, of the appropriate amine of formula HNR6R7 in solution in an inert solvent as defined above, preferably tetrahydrofuran.
• the reaction takes place at a temperature of about 0°-40°C., preferably about 20°-30°C., for about 1-10 hours, preferably about 4-6 hours.
• the product compound of formula (Ie) is isolated by conventional means such as chromatography.
• reaction is carried out in the presence of from 1-5 molar equivalents, preferably 2 molar equivalents, of a tertiary organic base or an inorganic base, as defined above.
• the compound of formula (XX) is reacted in the presence of the base with from 1-4 molar equivalents, preferably about 1.2 molar equivalents, of the appropriate amine of formula HNR6R7 in an inert organic solvent, as defined above.
• compounds of formula (Ie) are made directly from compounds of formula (VI), by reaction with an appropriately substituted carbamoyl chloride of formula ClC(O)NR6R7, where R6 and R7 cannot both be hydrogen.
• an inert organic solvent as defined above, preferably tetrahydrofuran, and reacted with from 1-4 molar equivalents, preferably about 1.2 molar equivalents, of the appropriate carbamoyl chloride of formula ClC(O)NR6R7 in the presence of a tertiary organic base or inorganic base as defined above.
• the reaction takes place at a temperature of about 0°-40°C., preferably about 20°-30°C., for about 1-10 hours, preferably about 4-6 hours.
• the product of formula (Ie) is isolated by conventional means such as chromatography.
• compounds of formula (Ie) where R7 is hydrogen can be made by reacting a compound of formula (VI) with an appropriately substituted isocyanate of formula R6NCO where R6 is not hydrogen.
• the compound of formula (VI) is dissolved in an inert organic solvent as defined above, preferably tetrahydrofuran, and reacted with from 1-5 molar equivalents, preferably about 1.2 molar equivalents, of an isocyanate of formula R6NCO in the presence of about 0.2 molar equivalents of 4-dimethylaminopyridine.
• the reaction takes place at a temperature of about 10°-70°C., preferably about 45-55°C., for about 4-48 hours, preferably about 18-24 hours.
• the product of formula (Ie) is isolated by conventional means such as chromatography.
• Reaction Sequence VIIIA to prepare the compound of formula (If), where X is -C(O)OR5, the activated carbonyl derivative of formula (XX), prepared as shown in Reaction Sequence VIIA above, is reacted with an alcohol of formula R5OH.
• an alcohol of formula R5OH containing from 1-5 molar equivalents, preferably about 2 molar equivalents of a tertiary organic base such as triethylamine or preferably pyridine.
• the reaction takes place at a temperature of about 0°-40°C., preferably about 20°-25°C., for about 1-10 hours, preferably about 4-6 hours.
• the product compound of formula (If) is isolated by conventional means.
• the compound of formula (VI) is reacted as shown above in Reaction Sequence VIIIA with an appropriate alkyl or aryl chloroformate, or alternatively with an appropriate dialkyl or diaryl dicarbonate, in the presence of a tertiary organic base.
• the compound of formula (VI) is dissolved in an inert solvent as defined above, preferably tetrahydrofuran, and reacted with a chloroformate and a tertiary organic base, preferably triethylamine.
• the reaction is conducted at a temperature of about 0-50°C, preferably about 20°-25°C, for about 4-48 hours, preferably about 18-24 hours, giving a compound of formula (If), which is isolated by conventional means.
• the compounds of formula HNR6R7 are commercially available from, i.a., Aldrich Chemical Co.. Alternatively, they can be prepared by standard methods known to those skilled in the chemical art.
• the compounds of formula ClC(O)NR6R7 are either available commercially from, i.a., Aldrich Chemical Co. or they can be prepared by, for example, reaction of a secondary amine of formula HNR6R7 with phosgene.
• Compounds of formula ClC(O)NR6R7 wherein R6 is hydrogen can be prepared by the reaction of an isocyanate of formula R7NCO with an excess of dry hydrochloric acid in an inert solvent. These reactions are described in greater detail in Comprehensive Organic Chemistry , Vol. 2, by Barton and Ollis, pp. 1088-1090.
• Any alkyl or aryl chloroformates that are not commercially available are prepared, for example, by reaction of phosgene with one equivalent of the appropriate alcohol or phenol in the presence of a base. The reactions are described in greater detail in Comprehensive Organic Chemistry , by Barton and Ollis, Vol 2, pp 1078-1083 and Vol 3, pp 432-4.
• R7NCO The compounds of formula R7NCO that are not commercially available are prepared by reaction of an appropriately substituted primary amine (R7NH2) with phosgene.
• R7NH2 an appropriately substituted primary amine
• the reaction is discussed in further detail in Organic Functional Group Preparations , 2nd Edition, Vol. 1, by Sandler and Karo, pp. 364-365.
• mice Male or female Swiss Webster mice weighing 18-27 g were randomly assigned to treatment groups of 8 or 10 animals, caged together, and given food and water ad libitum.
• test materials were prepared as solutions or suspensions in reagent grade acetone at a dose level of 100 mg/ml and arachidonic acid was prepared as a solution in acetone also at 100 mg/ml.
• the test materials were applied to the right ears of mice by means of an automatic microliter pipet so that 10 ⁇ l of solution was applied to each of the inner and outer surfaces. Each ear therefore received a total of 20 ⁇ l of solution containing 2 mg of test material.
• the arachidonic acid solution was applied in the same manner.
• the animals were sacrificed by cervical dislocation and the right ears were removed.
• mice weighing 23-27 g were used in groups of 10. On days 1 and 2 mice received 50 ul of a 2% solution of oxazolone in acetone applied to the unshaved abdomen (sensitization). On day six 25 ul of a 1.5% solution of oxazolone in acetone was applied to each side of the right ear (challenge). On day 7, 24 hr after challenge, the mice were euthanized and 8 mm diameter plugs obtained from the ears were weighed. Test materials were administered orally in aqueous vehicle 1 hr before challenge and again 6 hr after challenge.
• Toxicity of the compounds of the invention was assessed by acute subcutaneous dosing of rats, and observation for 17 days.
• Test compounds 2-methoxy-1,4-di(methylcarbamoyloxy)naphthalene 1-ethyl carbamolyloxy-2,4-diethoxynaphthalene

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